Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing.

Abstract

The mouse mutant jimpy carries an X chromosome-linked recessive gene defect that affects the formation of myelin in the central nervous system. To understand the molecular basis of the jimpy mutation, we have examined the expression of mRNAs encoding myelin proteolipid protein (PLP). PLP mRNAs were detectable in jimpy brain RNA at 21 days after birth but were severely reduced in abundance compared to wild-type littermates. Nucleotide sequence analysis of cDNA clones for PLP mRNA, isolated from a cDNA library of jimpy brain poly(A)+ RNA, revealed that the PLP mRNA expressed in jimpy contained a deletion of 74 nucleotides with respect to the wild-type sequence. This deletion causes a frameshift in the open reading frame resulting in an altered carboxyl terminus for jimpy PLP. Probes specific for the deleted sequence, however, hybridize with equal efficiency to genomic DNA from jimpy and wild-type littermates, suggesting that the defect in the jimpy PLP mRNA is generated by aberrant RNA processing rather than by deletion of genomic sequences. We conclude that a mutation in the gene for PLP that leads to an incorrectly spliced RNA transcript is the primary defect of this genetic disorder.Neurological mutants (1) are an important tool in developmental neurobiology as they may indirectly demonstrate the function of a single gene product in the development of the nervous system. In many mutant phenotypes, however, the primary defect is difficult to distinguish from secondary symptoms of the disease, and the affected gene product has been identified for only a few of the neurological mutations of the mouse. Identification of the nature of the mutation is essential for a full understanding of the molecular basis of the defect and of the role of the affected gene and its products in normal brain development.The mutant mouse jimpy (2, 3) carries an X-linked recessive genetic disorder (jp) that exclusively affects the formation of myelin in the central, but not in the peripheral, nervous system. Its first symptom, a characteristic body tremor preceding locomotor activity, appears around postnatal day 11, after the onset of myelination in the normal mouse brain. Later, convulsions develop and death occurs in the fifth week. Histological studies of jimpy mice reveal an almost complete absence of white matter in the central nervous system, and only some axons show more than a few sheaths of uncompacted myelin (4). Various biochemical abnormalities have been reported in the mutant, in particular a drastic decrease of structural myelin proteins and enzymes involved in myelin lipid metabolism (summarized in ref. 4). Myelin proteolipid protein (PLP), or lipophilin, is of particular relevance to the jimpy mutation because it is expressed specifically in the central nervous system (5) and is one of the most severely reduced myelin constituents of jimpy brains (6-9). Furthermore, the gene for PLP has been mapped to the X chromosome in both man and mouse (10). We have cloned and determined the full-length sequences of two mRNA...

Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin.

“…Its primary structure has been established by protein sequencing (2)(3)(4) and more recently from the cloning of PLP cDNAs from several species (5)(6)(7)(8)(9)(10). A mutation in the mouse PLP gene is the primary genetic defect of the dysmyelinating mutant mouse jimpy (8)(9)(10)(11)(12), which demonstrates the critical role of PLP in CNS myelin assembly.…”

Recovery of Myelin after Induction of Oligodendrocyte Cell Death in Postnatal Brain

“…Other models, involving experimental allergic encephalomyelitis, have been widely produced (Swanborg, 1995;Bradl and Linington, 1996;Stefferl et al, 2000). In addition, several spontaneous mutations of myelin genes are at the origin of myelin disorders in human (Snipes et al, 1993) and in jimpy, quaking, and shiverer mice (Friedrich, 1975;Roach et al, 1983, Nave et al, 1986Ghandour and Skoff, 1988;Hardy, 1998). Transgenic mice with silenced or overexpressed myelin genes were also used, and valuable information on the role of myelin proteins during development and in the adult were obtained (Kagawa et al, 1994;Nave, 1994;Readhead et al, 1994;Klugmann et al, 1997;Uschkureit et al, 2000).…”

Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpyMutant

“…Jp is an X-linked recessive mutation in the proteolipid protein (PLP) gene (Nave et al, 1986(Nave et al, , 1987Ikenaka et al, 1988). White matter tracts of the affected males show dysmyelination accompanied by increased proliferation of morphologically identified immature oligodendrocytes (Skoff, 1982) and increased oligodendrocyte death (Knapp et al, 1986), possibly attributable to abnormal PLP transport and accumulation (Gow et al, 1998).…”